Structure of the human MDR3 gene and physical mapping of the human MDR locus.
Structure of the human MDR3 gene and physical mapping of the human MDR locus.
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人类 MDR3 基因的结构和人类 MDR 基因座的物理图谱。
DOI：
10.1016/s0021-9258(19)67788-4
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Piet Borst
中科院分区：
文献类型：
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作者：
Carsten R. Lincke;J. Smit;T. D. Velde;Piet Borst
MDR1和MDR3两个基因构成了人类p -糖蛋白基因家族。为了研究三种已知哺乳动物p -糖蛋白基因之间的进化关系，我们克隆了MDR3基因，并将其结构与人类MDR1和其他研究小组分析的小鼠MDR1 （mdr1b）基因进行了比较。MDR3基因包含28个外显子，其中27个外显子包含与功能域相关的蛋白的两个同源半部分的编码序列。该结构与人类MDR1基因和小鼠MDR1 （mdr1b）基因的结构几乎相同，表明外显子/内含子结构在产生不同类别p糖蛋白的复制事件之前是固定的，但在p糖蛋白与相关基因分离之后，如囊性纤维化跨膜传导调节因子（CFTR）基因，具有完全不同的外显子/内含子结构。MDR3基因的四个选择性剪接转录本来自于外显子23和26的选择性剪接。我们分析了人类MDR基因座约120 kb的DNA克隆，包括整个MDR3基因（74 kb）和两个基因之间的基因间区域（34 kb），结合脉冲场凝胶电泳数据显示，人类MDR基因座约230 kb。与小鼠的mdr基因相比，两种人类基因的转录方向相同（MDR3位于MDR1的下游）。标记这两个基因5'端的富含cpg的序列在不同细胞系中存在不同程度的低甲基化。低甲基化大致与转录活性相关。
Two genes, MDR1 and MDR3, constitute the human P-glycoprotein gene family. To examine the evolutionary relationship between the three known classes of mammalian P-glycoprotein genes, we have cloned the MDR3 gene and compared its structure with that of the human MDR1 and the mouse mdr1 (mdr1b) genes analyzed by other groups. The MDR3 gene contains 28 exons and 27 of these contain coding sequences for the two homologous halves of the protein that correlate with functional domains. This structure is virtually identical to that of the human MDR1 gene and the mouse mdr1 (mdr1b) gene, indicating that the exon/intron structure was fixed before the duplication events that generated different classes of P-glycoproteins, but after the P-glycoproteins diverged from related genes, like the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which has an entirely different exon/intron structure. The four alternatively spliced transcripts of the MDR3 gene arise from alternative splicing of exons 23 and 26. Our analysis of DNA clones covering about 120 kilobases (kb) of the human MDR locus, including the entire MDR3 gene (74 kb) and the intergenic region between both genes (34 kb), combined with pulsed-field gel electrophoresis data shows that the human MDR locus covers about 230 kb. In contrast to the mouse mdr genes, both human genes are transcribed in the same direction (MDR3 located downstream of MDR1). The CpG-rich sequences marking the 5' ends of both genes are hypomethylated to different extents in different cell lines. Hypomethylation roughly correlates with transcriptional activity.